PROJECT SUMMARY/ABSTRACT Knee osteoarthritis (OA) is a major public health problem, causing substantial pain and functional limitations, yet few effective therapies are available to improve pain and function. Non-invasive treatments are needed to improve quality of life and decrease the need for total knee arthroplasty. Abnormal mechanical loading is a well-recognized cause of knee OA and many rehabilitation treatments aim to improve abnormal loading. Impact loading is one such factor that can be intervened upon to potentially improve pain and function. While gait retraining strategies have been shown to improve the knee adduction moment, it is unknown if gait retraining can change impact loading and improve knee pain in older individuals with knee OA. Individuals with painful knee OA also demonstrate a heightened response to normally non-painful stimuli (i.e., sensitization) and impaired descending inhibition of pain, both of which contribute to greater pain severity. It is unknown, however, whether these alterations in the sensory nervous system also affect the motor efferent nervous system, with resulting adverse effects on motor function. Furthermore, the presence of altered pain processing may modify the effect of traditional rehabilitation strategies. Such insights would provide opportunities for tailoring individual rehabilitation strategies. The specific aims of the proposed work are: 1) To evaluate the relation of altered pain processing, independent of knee pain severity, to impact loading (e.g., peak impact force and loading rate from the ground reaction force) during walking, 2) To determine whether a gait retraining program decreases impact loading and knee pain in individuals with knee OA, and 3) To determine whether altered pain processing modifies the effect of gait retraining on impact loading. For specific aim 1, we will leverage data from the NIH funded Multicenter Osteoarthritis Study (MOST), a cohort study of ~3000 individuals with or at risk of knee OA, in which measures of pain sensitization and ground reaction forces (GRFs) during gait have been assessed. Measures of impact loading will be determined from GRFs. For specific aim 2 and 3, subjects will be recruited locally and undergo biomechanical and pain assessments at baseline and follow-up. Subjects will be a randomized to either a control walking intervention or a walking program with gait retraining. The retraining will involve verbal feedback to soften footfalls and real-time visual feedback to decrease tibial acceleration (a correlate of knee loading) using an accelerometer while walking on a treadmill. Primary and secondary outcomes include measures of impact loading and knee pain, respectively. The proposed research is highly significant in that it will directly affect the clinical management of individuals with knee OA. This proposal will provide Dr. Stefanik new training and mentorship in the neurobiology of pain, biomechanics and motion analysis methodology, gait retraining and conducting a clinical intervention study, which builds upon his previous research experience in clinical epidemiology. This training will be integral in assisting Dr. Stefanik to meet his long-term career goal of developing novel and effective rehabilitation interventions for individuals with knee OA.